Placenta growth factor stimulates MAP kinase and mitogenicity but not phospholipase C-gamma and migration of endothelial cells expressing Flt 1.
Vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) are structurally related growth factors for endothelial cells. VEGF binds to the related receptor tyrosine kinases Flt 1 and KDR/Flk 1 with high affinity, whereas PlGF binds only to Flt 1. Ligand-stimulated KDR is known to transduce signals for cellular activity such as proliferation and migration, whereas weak or no responses have been recorded for Flt 1. We examined VEGF and PlGF for their capacity to stimulate signal transduction in porcine aortic endothelial cells expressing Flt 1 or KDR. VEGF had essentially no effect on Flt 1 expressing cells, but induced DNA synthesis and migration of KDR expressing cells. PIGF on the other hand induced DNA synthesis but not migration of the Flt 1 cells. In agreement, MAP kinase, examined as a marker for DNA synthesis, was activated both by VEGF-stimulation of the KDR cells and by PlGF-stimulation of the Flt 1 cells. In contrast, phospholipase C-gamma (PLC-gamma), was tyrosine phosphorylated only in VEGF stimulated KDR cells, and not in the PlGF-stimulated Flt 1 cells, which is in agreement with a role for PLC-gamma in cellular migration. We furthermore examined induction of protein levels of plasminogen activator (PA), which was evident in the PlGF-stimulated Flt 1 cells, but not in the VEGF-stimulated KDR cells. These data show that Flt 1 is able to mediate an array of biological signals when appropriately stimulated and that the pattern of responses of PlGF-stimulation of Flt 1 is distinct from the pattern of responses to VEGF-stimulation of KDR.
Landgren
E
E
Dept. of Medical and Physiol. Chemistry Biomedical Center, Uppsala, Sweden.
Schiller
P
P
Cao
Y
Y
Claesson-Welsh
L
L
D000818:Animals; D001011:Aorta / Q000166:cytology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008222:Lymphokines / Q000494:pharmacology; D008934:Mitogens / Q000494:pharmacology*; D051966:Phospholipase C gamma; D010766:Phosphorylation; D000072483:Placenta Growth Factor; D010960:Plasminogen Activators / Q000096:biosynthesis / Q000378:metabolism; D011257:Pregnancy Proteins / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000096:biosynthesis / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor; D013552:Swine; D010738:Type C Phospholipases / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D007527:Isoenzymes; D008222:Lymphokines; D008934:Mitogens; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000072483:Placenta Growth Factor; D014443:Tyrosine; D004247:DNA; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D010960:Plasminogen Activators